Project Summary/Abstract We have recently identified that circulating adiponectin levels negatively correlate with albuminuria in obese African Americans. As the incidence of kidney disease is extremely high in African Americans and the mechanisms of obesity related kidney disease are unclear, our proposal will focus on this highly significant topic to the VA population. The podocyte appears to be the main target cell by which adiponectin confers its protective action. In the present proposal we will identify the adiponectin receptors and signaling pathways by which adiponectin confers benefits to the podocytes and examine the key role of adiponectin in regulating an enzyme called AMPK. We have identified that AMPK is decreased in adiponectin deficient mice and in podocytes from diabetic mice. Administration of adiponectin restores AMPK activity and appears to protect podocytes from albuminuria. A key target of AMPK on podocytes appears to be the protein ZO-1 which has been shown to be intimately involved in the adherence of the podocyte foot processes to the glomerular basement membrane. The proposal aims to identify the key signaling receptors for adiponectin on podocytes, identify the role of AMPK and identify the proteins regulated by adiponectin and AMPK in mice. The studies will be of direct benefit to the VA population as there are existing drugs that regulate adiponectin levels and its signaling pathways, and thus may potentially offer new therapies for this population that is at high risk for kidney disease.